Adenovirus-mediated delivery of siRNA targeting TM4SF4 attenuated liver cancer cell growth <italic>in vitro</italic> and <italic>in vivo</italic>

Abstract

Gene targeting using short interfering RNA (siRNA) has become a common strategy to explore gene function because of its prominent efficacy and specificity. The human transmembrane 4 superfamily member 4 (TM4SF4) was originally identified in intestine and liver as a cell proliferation-related gene. Recently, it showed an increased expression in the hepatocellular carcinoma (HCC) tissues. In this study, we developed an adenoviral vector harboring an effective siRNA targeting TM4SF4 (AdSiTM4SF4) and identified its function in suppression of tumor cell growth. It was confirmed that TM4SF4 was overexpressed in HCC tissues compared with its paired non-tumor tissues by western blot analysis and immunohistochemistry. Remarkably, it was more abundant on the cell surface of HCC cells. The signals of ectopically expressed TM4SF4 in four cell lines dramatically localized in the plasma membrane, slightly in the cytoplasm, and absent in the nucleus, demonstrating that TM4SF4 is a membrane protein. Targeting TM4SF4 by AdSiTM4SF4 successfully exerted a gene knockdown effect. The QGY-7701 and SMMC-7721 HCC cells infected with AdSiTM4SF4 displayed remarkably attenuated growth potential.Moreover, intratumoral injection of AdSiTM4SF4 significantly suppressed tumor growth in a xenograft mouse model using SMMC-7721 hepatoma cells. Our results indicated that targeting TM4SF4 might be a promising modality for inhibition of HCC.

Role of Transmembrane 4 L Six Family 1 in the Development and Progression of Cancer

“…TM4SF4 triggered OPN expression by creating a positive feedback autocrine loop with JAK2/STAT3 or focal adhesion kinase (FAK)/STAT3 pathways. Blocking the activity of TM4SF4 using specific antibody and short interfering RNA (siRNA) can be a promising therapeutics against TM4SF4-overexpressing cancer (Wang et al, 2013;Choi et al, 2014).…”

Osteopontin production by TM4SF4 signaling drives a positive feedback autocrine loop with the STAT3 pathway to maintain cancer stem cell-like properties in lung cancer cells

“…Although its structural features imply different functions compared to other members of transmembrane 4 superfamily, there are few studies on TM4SF4 yet except its expression in the liver or intestine [ 18 ]. Overexpression of TM4SF4 is shown in hepatocellular carcinoma and colorectal cancer [ 19 , 20 ] and targeting TM4SF4 with siRNA attenuates the cell growth of hepatocellular carcinoma [ 21 ] which implies TM4SF4 is a potential anti-cancer target. In our previous study, we showed TM4SF4 expression is elevated in non-small cell lung cancer cells (NSCLC) via loss of promoter methylation and confers γ-radiation resistance through activation of the IGF1Rβ/PI3K/AKT/NFκB pathway [ 22 ].…”

Preventive effects of siRNA targeting PPARγ gene on steroid-induced osteonecrosis in rabbits

“…Furthermore, adenoviral integration events and integration mutations are rare (47,48). Currently, the delivery of siRNA into target tissues for the interference in expression of disease-related specific genes by using adenoviral vectors has yielded satisfactory results (12)(13)(14)(15).…”

“…The adenovirus genome is highly homologous with the human genome. Currently, the delivery of siRNA into target tissues for the interference of expression of disease-related specific genes using an adenoviral vector has achieved satisfactory results (11)(12)(13)(14). However, to our knowledge, there is no report of siRNA targeting the PPARg gene aimed at preventing steroidinduced ONFH.…”